Journal of Medical Hypotheses and Ideas最新文献

Tolerability is an essential part of drug therapy and can affect health and economic outcomes. Withdrawal due to adverse reactions of medicines or lack of effectiveness is a major concern in long-term treatments that influences cost-effectiveness analysis. In case of possibility of stopping and switch to other interventions in decision analysis model, overhead costing may affect results and decision-making processes. Thus, modifying of classic decision analysis model seems to be necessary in such cases. My hypothesis is that by the use of a new decision model that can make links between different Markov-like models accurate cost calculation could be achieved. The appearance of model is going to be like a semicycle net. Considering the probability of switching from one treatment strategy to another, one could give more precise economic evaluation results. In the first step, this model needs to be tested and compared with the conventional model. In the second step, the impact of these differences has to be examined in the practical field of health, drug policy and supply management. By applying this new decision model in total health budget, threshold and its consequences on national health accounts and share of health in gross domestic product should be tested.

The brown adipose tissue (BAT) is an organ with the specialised function of intracellular fat oxidation; in other words, brown fat points to a potential natural tool by which energy expenditure is being stimulated. Obesity is a serious illness which can lead to many medical complications such as cardiovascular disorders. The BAT production, therefore, could be a promising therapeutic strategy for managing obesity. While different approaches have been examined to generate brown adipocytes from various precursor cells, no study has proposed an efficient procedure for direct trans-differentiation of white to brown adipocytes. Bone morphogenic protein (BMP)-7 is a possible potential agent by which most of the main factors involved in induction of brown adipocytogenesis such as early regulators of brown fat fate, positive regulatory domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1α) are stimulated, but the rate of success was not so promising. It has been documented that mature white adipocytes exert endoplasmic reticulum stress response (ESR) and consequently unfolded protein response (UPR) becomes activated for the purpose of ESR recovery since the ESR exceeds the capacity of UPR to overcome the imposed stress, and in turn disables the cell to manage the protein synthesis cascade including those required for BMP-7 induction of brown adipogenesis. This was performed using three main ESR sensors: PKR-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme-1 (IRE-1) and activating transcription factor 6 alpha (ATF-6α) resulting in attenuation of protein translation by blocking the activation of transcriptional machinery of UPR genes and the cell behaviour would also be changed towards apoptosis.

It may suggest and propose the hypothesis that pretreatment of the white adipocyte with an ESR inhibitor such as salubrinal by reducing ESR and turning on the protein synthesis machinery required for BMP-7 induction of brown adipogenesis cascade could provide a more efficient and successful method of transdifferentiation procedure of white to brown adipocytes.

Abstract

Organophosphate pesticides (OPs) inhibit both true and pseudo-cholinesterases by reaction with the hydroxyl group of serine in their active sites. Poisoning with OPs is commonly seen in clinics. A common antidote for OP poisoning is atropine but, after ageing and OP dealkylation, even oximes could not be effective. It has been shown that oximes are not always useful in management of OP poisoning. On the other hand, magnesium has been found effective in both clinical and experimental studies. Studies to find more effective antidotes for OP poisoning are in progress. Presently, the possible role of magnesium ion in catalysis of reaction of dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP), a water-soluble OP, with serine is proposed. The hydroxyl group of serine could be a target to which DDVP can react. Nucleophilic attack of pralidoxime to DDVP was previously investigated. To confirm the idea, data were derived from recent and previous research on the role of magnesium in phosphoryl group transfer reactions. Possible reactions of serine and pralidoxime with DDVP in the absence and the presence of magnesium ion were separately investigated theoretically.

We propose that the chemical reaction of serine with DDVP exclusively occurs in the presence of a magnesium divalent cation, whereas the reaction of pralidoxime with DDVP occurs independent of the presence of the magnesium ion. The role of the dissociation constant (pK_a) of functional groups in these reactions seems important.

It is suggested that application of serine in combination with the magnesium cation can become a more efficient antidote for treatment of OP poisoning.

Cancer is a leading cause of death worldwide. Interventional cancer therapy made huge progress in the past few decades; however, traditional interventional therapy, for example, transarterial embolisation and transarterial chemoembolisation, remains to be developed for its potential limitations. Numerous studies in the past half century demonstrated that tissue injury accelerated after ischaemia reperfusion. Reactive oxygen species (ROS) production, cell death and inflammatory factors involved in the development of ischaemia reperfusion injury. As outlined above, we hypothesise that reperfusing the tumour lesion with high oxygen, high calcium and high pH fluid together with ROS-generating agents and/or inhibitor of antioxidant system, with or without traditional chemotherapeutic agents after a short-time arterial embolisation, can effectively induce cancer cell death, and it might be a new attempt in cancer interventional therapy.

Behçet’s disease (BD) is a systemic vasculitis which is characterised by oral, aphthous ulcers, genital ulcers, skin lesions and ocular manifestations. Although the aetiopathogenesis of BD is still unknown, the critical role of Th1 immune responses, neutrophil hyperactivation alongside overproduction of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-8, tumour necrosis factor-alpha (TNFα) and particularly IL-17 have been demonstrated in the immunopathogenesis of the disease. Despite significant progress in understanding of the aetiology of the disease, its treatment remains intricate, and is still treated with immune-suppressive drugs and biological agents with probable systemic side effects. Accordingly, there is a necessity to establish the more efficient and less toxic therapeutic methods which may offer a long-time remission of BD.

Mesenchymal stem cells (MSCs) are non-haematopoietic and multipotential stem cells with immunosuppressive capacities in innate and acquired immune systems. MSCs can migrate to damaged tissues and prevent secretion of proinflammatory cytokines and other immunomodulatory effectors, increasing the survival of damaged cells, although the exact underlying mechanisms are still unknown. For this purpose, numerous herpes simplex viruses are injected into C57BL/6 mice to produce Behçet’s mouse model and transferring a certain number of MSCs may have therapeutic value for control of Behçet’s animal model, so researchers could deliberate the function of MSCs and proinflammatory cytokines particularly IL-17A-F, TNF-α, interferon gamma (IFN-γ), IL-2, IL-6 and IL-8 in an experimental model.

The aim of this hypothesis is to evaluate immunosuppressive and immunomodulatory properties of MSCs in syngeneic animal model for BD, in order to clarify the mechanisms of MSCs in BD management, as a broad and more confident treatment in clinical application.

Leakage from anastomosis site and low anterior resection syndrome are serious complications that may occur after low anterior resection for low rectal cancers. Although surgeons recommended different surgical and medical solutions for decreasing these complications, they are not successful in some cases. We think using the ileal pouch with vascular pedicle instead of devascularised and denervated left colon to anastomosis to anal canal may diminish these two problems. It needs more animal studies and then clinical trials to evaluate this new technique.

The anticancer activity demonstrated by genetically attenuated invasive Shigella flexneri contradicts the long-held understanding of bacterial infection-mediated anticancer activity (BIMAc), as a ‘by-stander effect’ caused by an immune response against any invading pathogen as a reason for tumour regression. Similarly, the selective tumouricidal effect by Salmonella A1 auxotrophic mutant in nude mice is another observation where the current theory fails. Considering these flaws, we set to re-examine the mechanisms behind BIMAc independent of immune response, on the basis of molecular understanding about the initial colonisation of gut epithelium by S. flexneri and its production of cell-cycle-inhibiting proteins called cyclomodulins. During infection, S. flexneri injects OspE effector protein into the gut epithelium. The resulting interaction of OspE with ILK prevents epithelial cell exfoliation and facilitates the pathogen’s colonisation of the gut. This interaction is also shown to enhance membrane retention of ILK in these infected cells. Correspondingly, another study reports the indispensable role of ILK in survival of cancer cells with supernumerary centrosomes by localising it to the centrosomes and clustering them into a bipolar spindle. Knockdown of ILK in these cells leads to apoptosis due to multipolar mitosis. From these cumulative facts we hypothesised that enhanced membrane retention of ILK in Shigella-infected cancer cells prevents localisation of ILK to centrosomes and provokes multipolar mitosis and therefore cell death in cancer subpopulations with supernumerary centrosomes. This interaction may also be metastasis suppressive, because of its inhibitory effect on the focal adhesion turnover of gut epithelium, which is quintessential for any form of cell migration. Apart from these, Shigella also encodes potent cell-cycle-inhibiting effector molecules such as cyclomodulins. The additive action of these cyclomodulins along with the OspE–ILK interaction may be considered as the reason behind the anticancer activity mediated by Shigella infection.

Metal phosphides in general are potent pesticides that are a common cause of human poisoning. Various salts of phosphides produce highly toxic phosphine in exposure to gastric acid that results in multi-organ damage and death. There is no antidote for phosphine poisoning and most of human poisoned cases do not survive. All we know so far is that phosphine is a mitochondrial toxin that inhibits cellular respiration and induces oxidative stress. Mechanistically, phosphine as a reducing agent interacts with metal ion cofactors at the active site of enzymes and inhibits key enzymes such as cytochrome C oxidase that lead to inhibition of mitochondrial respiration. Phosphine (E0 = −1.18 V) as a reducing agent gives electrons to cytochrome C oxidase (E0 = +0.29 V). Metal phosphides with lower reduction potential are stronger electron donors and thus stronger poisons. Our hypothesis is that if an electron receiver stronger than cytochrome C oxidase is used then it would compete with cytochrome C oxidase in interaction with phosphine. This competition might prevent or reduce the inhibition of cellular respiration. This idea can be tested in an animal model of phosphine toxicity by monitoring cardiovascular state and measuring the cardiac mitochondrial function.

Caesarean rate has been increasing year by year in China and other countries in the world. In fact, caesarean section is associated with increased risk of maternal mortality and serious foetal pulmonary morbidity. To reduce caesarean rate, obstetricians in physician-based birth units get used to take early intervention for any delay in labour progress that could cause dystocia. However, standard obstetric care enhanced by obstetric power has not consistently been shown to reduce rate of caesarean delivery. Other than physician-based model, midwife-led model of care is aiming to promote normal birth by use of midwives’ skills as well as continuous support rather than augmentation of labour through excessive medical treatment. Midwife-led care model is novel to worldwide birth units where standard obstetric care still dominates. It has made some headway in efforts to reduce caesarean rate. The fact that standard obstetric care of childbirth have not consistently reduced rate of caesarean delivery encourages us for creating the hypotheses that midwife-led care model satisfying puerpera with care and support could minimise unnecessary obstetric intervention and facilitate vaginal birth, and finally reduces caesarean rate. This hypothesis, if confirmed, might have the potential to be disseminated elsewhere in the world, where most women still take standard obstetric care. Moreover, it has political implications for the national health-care policymaking.